Abstract
ABSTRACTThe Deciphering the Mechanisms of Developmental Disorders (DMDD) program uses a systematic and standardised approach to characterise the phenotype of embryos stemming from mouse lines, which produce embryonically lethal offspring. Our study aims to provide detailed phenotype descriptions of homozygous Col4a2em1(IMPC)Wtsi mutants produced in DMDD and harvested at embryonic day 14.5. This shall provide new information on the role Col4a2 plays in organogenesis and demonstrate the capacity of the DMDD database for identifying models for researching inherited disorders. The DMDD Col4a2em1(IMPC)Wtsi mutants survived organogenesis and thus revealed the full spectrum of organs and tissues, the development of which depends on Col4a2 encoded proteins. They showed defects in the brain, cranial nerves, visual system, lungs, endocrine glands, skeleton, subepithelial tissues and mild to severe cardiovascular malformations. Together, this makes the DMDD Col4a2em1(IMPC)Wtsi line a useful model for identifying the spectrum of defects and for researching the mechanisms underlying autosomal dominant porencephaly 2 (OMIM # 614483), a rare human disease. Thus we demonstrate the general capacity of the DMDD approach and webpage as a valuable source for identifying mouse models for rare diseases.
Highlights
IntroductionThe heart of Developmental Disorders (DMDD) is the characterisation of the phenotype of embryos harvested at embryonic day (E) 14.5
Together with Col4a1, Col4a2 encodes extracellular matrix proteins, which participate in the macromolecular network of basement membranes (Hudson et al, 1993; Jeanne and Gould, 2017; Khoshnoodi et al, 2008; Sado et al, 1998)
This study aims to present detailed descriptions of the morphological phenotype of the Col4a2 mutants and examine the implications of the Developmental Disorders (DMDD) project in identifying and researching models of rare diseases by using autosomal dominant porencephaly type 2 as an example
Summary
The heart of DMDD is the characterisation of the phenotype of embryos harvested at embryonic day (E) 14.5 At this developmental stage, organogenesis is complete and comprehensive analysis of the role gene products play in organ formation is possible, even if defects resulting from gene mutation cause death in the foetal or perinatal period (Geyer et al, 2017b; Wilson et al, 2017). Amorphous, specialised extracellular matrices, which function as an anchor for epithelial cells (Pozzi et al, 2017) They are essential components of all vessels and many organs and play a vital role in diverse biological events including embryogenesis, tissue remodelling, wound healing, protection of tissues and organs from exogenous factors, resistance to mechanical stress, and filtration of blood and air (Sado et al, 1998)
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